ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2653C>T (p.Gln885Ter) (rs63750808)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076535 SCV000107564 pathogenic Lynch syndrome I 2018-06-13 reviewed by expert panel curation This variant is before the cutoff (codon 888) and therefore Class 5
GeneDx RCV000202119 SCV000322359 pathogenic not provided 2018-07-17 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2653C>T at the cDNA level and p.Gln885Ter (Q885X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG). This variant has been reported in several individuals with colon cancer and in one with ovarian cancer (Taylor 2003, Wagner 2003, Evans 2009, Schofield 2012, Hampel 2018). Due to the position of the variant, nonsense mediated decay is not expected to occur, but it might cause loss of normal protein function through protein truncation. The disrupted region at the end of the gene contains the helix-turn-helix domain and the region of interaction with MSH6 and MSH3 (Guerrette 1998, Lutzen 2008, Kansikas 2011). Additionally, Wielders et al. (2017) found that MSH2 variants lacking the c-terminus severely destabilize MSH2/MSH6 interaction and result in increased microsatellite instability. MSH2 Gln885Ter was not observed in large population cohorts (Lek 2016). Based on currently available evidence, we consider this variant to be pathogenic.
Ambry Genetics RCV000491409 SCV000580400 pathogenic Hereditary cancer-predisposing syndrome 2019-03-15 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202119 SCV000257182 pathogenic not provided no assertion criteria provided research

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